Abstract

Buprenorphine is a mixed opioid receptor agonist-antagonist used
clinically for maintenance therapy in opiate addicts and pain
management. Dose-response curves for buprenorphine-induced
antinociception display ceiling effects or are bell shaped, which have
been attributed to the partial agonist activity of buprenorphine at
opioid receptors. Recently, buprenorphine has been shown to activate
opioid receptor-like (ORL-1) receptors, also known as OP4 receptors.
Here we demonstrate that buprenorphine, but not morphine, activates
mitogen-activated protein kinase and Akt via ORL-1 receptors. Because
the ORL-1 receptor agonist orphanin FQ/nociceptin blocks opioid-induced
antinociception, we tested the hypothesis that buprenorphine-induced
antinociception might be compromised by concomitant activation of ORL-1
receptors. In support of this hypothesis, the antinociceptive effect of
buprenorphine, but not morphine, was markedly enhanced in mice lacking
ORL-1 receptors using the tail-flick assay. Additional support for a
modulatory role for ORL-1 receptors in buprenorphine-induced
antinociception was that coadministration of J-113397, an ORL-1
receptor antagonist, enhanced the antinociceptive efficacy of
buprenorphine in wild-type mice but not in mice lacking ORL-1
receptors. The ORL-1 antagonist also eliminated the bell-shaped
dose-response curve for buprenorphine-induced antinociception in
wild-type mice. Although buprenorphine has been shown to interact with
multiple opioid receptors, mice lacking mu-opioid receptors failed to
exhibit antinociception after buprenorphine administration. Our results
indicate that the antinociceptive effect of buprenorphine in mice is
mu-opioid receptor-mediated yet severely compromised by concomitant
activation of ORL-1 receptors.